This article is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 07 meeting in Washington, DC. The presentations discussed the phenomenology, clinical consequences, and underlying mechanisms of cytochrome P450 and drug transporter regulation by inflammatory and infectious stimuli. Although considerable insights into the links between inflammatory mediators and altered hepatic drug clearance pathways have been gained from previous studies with acute inflammatory stimuli, this symposium highlighted recent advances in understanding how these processes operate in other organs and chronic inflammatory states relevant to human diseases. The development of mouse models of live bacterial infection provides excellent opportunities to explore the impact of infection on drug metabolism beyond the well characterized effects of bacterial endotoxin. Altered levels of cytochromes P450 and especially drug transporters due to inflammation in brain, intestine, and placenta have significant implications for the use of many drugs in diverse clinical settings. The consequences of inflammatory cytokine production by tumors for drug safety and efficacy in cancer patients were outlined. Repression of drug clearance pathways by tumor-derived cytokines may result in extreme toxicity to chemotherapy, compromising treatment of many cancers. It is fitting that, in honoring the career contributions and achievements of Dr. Kenneth W. Renton, this symposium reinforced the clinical relevance of this field.

Cancer has become one of the most difficult health challenges of our time, accounting for millions of deaths yearly. Systemic chemotherapy is the most common therapeutic approach; however, considerable limitations exist including toxicities to healthy tissues and low achievable drug concentrations at tumor sites. More than 85% of human cancers are solid tumors, which can greatly benefit from localized delivery. This approach allows for high drug concentrations at the target site, lower systemic toxicity, and extended drug exposure which may be beneficial for cell cycle-specific drugs. Polymers have been widely considered in the development of localized delivery systems. This review focuses on both natural and synthetic biodegradable polymers that have been explored for localized chemotherapy, exploring their advantages, disadvantages, and clinical potential while citing examples of their use in pre-clinical development.

Endotoxin-mediated cholestasis stems from impaired hepatobiliary transport of bile acids and organic anions due to altered expression and activity of transporters, including Oatp,Mrp, Ntcp, and Bsep. However, the mechanisms by which the Oatp andMrp genes are down-regulated are largely unknown. Using in vivo and in vitro murine models of inflammation, we examined the role of cytokines and bile acids in regulating Oatp andMrp. Endotoxin (lipopolysaccharide, LPS), interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, cholic acid, taurocholate, or taurodeoxycholate was administered in vivo to mice or in vitro to Hepa 1-6 mouse hepatoma cells. Mrp,Oatp, and Bsep mRNA levels were measured by reverse transcription-polymerase chain reaction.Mrp efflux activity was measured using 5-carboxyfluorescein. In vivo, LPS treatment profoundly suppressed hepatic mRNA levels of Mrp2, Mrp3,Oatp1, Oatp2, and Bsep to 15, 60, 44, 30, and 32% of controls, respectively (p < 0.05), but did not significantly alterMrp1 expression. IL-6 or IL-1β administration suppressed Mrp2, Oatp1,Oatp2, and Bsep mRNA levels to 20 to 60% controls (p < 0.05). TNF-α administration affected mRNA levels of Mrp2, Mrp3, andOatp2 but not Oatp1 orBsep. Bile acid treatment increased the in vivo expression of Bsep but not Mrp orOatp. Likewise, significantly lower mRNA levels ofMrp2 with a corresponding decrease in cellular efflux of 5-carboxyfluorescein was seen in vitro in IL-6- and IL-1β-treated Hepa 1-6 cells, whereas bile acids did not have significant effects. In conclusion, cytokines are key mediators in regulating hepatic expression of anion transporters in inflammatory cholestasis, whereas bile acids likely play a minor role.

Inflammation and proinflammatory cytokines suppress the expression of several hepatic transporters and metabolic enzymes, often resulting in cholestatic liver disease. However, mechanism(s) of this down-regulation have not been fully elucidated. As the pregnane X receptor (PXR) is involved in inducing many of these hepatic proteins, it is possible that PXR is also involved in their down-regulation during inflammation. Thus, we compared the effect of inflammation on hepatic gene regulation in wild-type (PXR^+/+) versus PXR-null (PXR^-/-) mice. Treatment of PXR^+/+ but not PXR^-/- mice with the PXR activators 5-pregnen-3β-ol-20-one-16α-carbonitrile (PCN) or 17β-hydroxy-11β-[4-dimethylamino phenyl]-17α-[1-propynyl] estra-4,9-dien-3-one (RU486) resulted in increased mRNA levels of bsep, mdr1a, mrp2, mrp3, oatp2, and cyp3a11, indicating involvement of PXR in their regulation. Significantly lower mRNA levels of bsep, mdr2, mrp2, mrp3, ntcp, oatp2, and cyp3a11 were found in endotoxin-treated PXR^+/+ mice. In endotoxin-treated PXR^-/- mice, the extent of mrp2 suppression was significantly diminished. Changes in MRP2 expression were supported by Western blot analysis. Although interleukin (IL)-6 imposed significant decreases in the expression of bsep, mrp2, and cyp3a11 in PXR^+/+ mice, this was not observed in PXR^-/- mice. Of note, significantly lower levels of PXR mRNA and protein were detected in endotoxin- and IL-6-treated PXR^+/+ mice. In addition, endotoxin and IL-6 were also able to suppress PCN-mediated induction of bsep, mrp2, cyp3a11, and PXR. Taken together, our results suggest that PXR plays a role in the down-regulation of several hepatic proteins during inflammation.

Inflammation-induced changes in the pharmacokinetics and dynamics of numerous drugs have been reported. Altered drug disposition during inflammatory disease has traditionally been ascribed primarily to changes in drug metabolism and protein binding. Emerging evidence within the last decade, however, has demonstrated that the inflammatory response affects the expression of several important drug transporters and these changes significantly impact the disposition and activity of drug substrates.